Isoureas and isothioureas

ABSTRACT

The compounds are isoureas and isothioureas which have an O- or S- alkylpyrimidone substituent and which are histamine H 2  -antagonists and antiinflammatory agents. A specific compound of this invention is 2-[5-(O-isoureido)pentylamino]-5-(6-methyl-3-pyridyl-methyl)-4-pyrimidone.

This is a division of application Ser. No. 056,171 filed July 10, 1979,now U.S. Pat. No. 4,305,945.

This invention relates to pyrimidine compounds, to pharmaceuticalcompositions containing them and to methods of blocking histamine H₂-receptors by administering them.

Many physiologically-active substances elicit their biological actionsby interaction with specific sites known as receptors. Histamine is sucha substance and has multiple biological actions. Those biologicalactions of histamine which are inhibited by drugs commonly called"antihistamines" (histamine H₁ -antagonists), of which mepyramine,diphenydramine and chlorpheniramine are typical examples, are mediatedthrough histamine H₁ -receptors. However, others of the biologicalactions of histamine are not inhibited by "antihistamines" (histamine H₁-antagonists) and actions of this type which are inhibited by burimamideare mediated through receptors which are termed histamine H₂ -receptors.In this specification by histamine H₂ -receptors is meant receptorsdefined by Black et al. (Nature, 236, 385 (1972)) as those histaminereceptors which are not blocked by mepyramine but are blocked byburimamide. Compounds which block histamine H₂ -receptors are referredto as histamine H₂ -antagonists.

Blockade of histamine H₂ -receptors is of value in inhibiting thebiological actions of histamine which are not inhibited by"antihistamines" (histamine H₁ -antagonists). Histamine H₂ -antagonistsare active, for example, as inhibitors of gastric acid secretion, asanti-inflammatory agents and as agents which act on the cardiovascularsystem, for example as inhibitors of the effects of histamine on bloodpressure.

In some physiological conditions the biological actions of histamine aremediated through both histamine H₁ - and H₂ -receptors and blockade ofboth types of receptors is useful. These conditions include inflammationmediated by histamine, for example skin inflammation, and thosehypersensitivity responses due to the action of histamine at H₁ - and H₂-receptors, for example allergies.

The pyrimidine compounds of the present invention are histamine H₂-antagonists and also have histamine H₁ -antagonist activity andantiinflammatory activity.

The present invention provides pyrimidines of Structure 1: ##STR1## inwhich R¹ and R² (which may be the same or different) are hydrogen orlower alkyl or together with the carbon and two nitrogen atoms shownform a dihydroimidazolyl or tetrahydropyrimidyl group:

Y is sulphur or oxygen;

n is from 3 to 8;

X is oxygen or sulphur;

Z is hydrogen or lower alkyl;

A is straight or branched C₁ --C₅ alkylene or --(CH₂)_(p) W(CH₂)_(q)--where W is oxygen or sulphur and the sum of p and q is 1 to 4; and

B is methyl, C₃ -C₆ cycloalkyl, a heteroaryl group optionallysubstituted by one or more (which may be the same or different) loweralkyl, lower alkoxy, halo, hydroxy or amino groups, or B is a naphthyl,5- or 6-(2,3-dihydro-1,4-benzodioxinyl), or a 4- or5-(1,3-benzodioxolyl) group, or a phenyl group optionally substitutedwith one or more (which may be the same or different) lower alkyl, loweralkoxy, halogen, aryl(lower alkoxy) (preferably phenyl(lower alkoxy),for example benzyloxy), hydroxy, lower alkoxy-lower alkoxy,trifluoromethyl, di(lower alkyl)amino, phenoxy, halophenoxy, loweralkoxyphenoxy, phenyl, halophenyl or lower alkoxyphenyl groups, or,provided A is alkylene, B can be hydrogen.

The compounds of Structure 1 can be in the form of the free bases ortheir pharmaceutically acceptable acid addition salts.

Throughout this specification by the terms `lower alkyl` and `loweralkoxy` are meant alkyl and alkoxy groups which can be straight orbranched and which contain 1 to 4 carbon atoms. Particular lower alkylgroups are methyl, ethyl, 1-propyl and 2-propyl. Particular lower alkoxygroups are methoxy, ethoxy, 1-propoxy and 2-propoxy.

Examples of heteroaryl groups B are pyridyl, N-oxopyridyl, furyl,thienyl, thiazolyl, oxazolyl, isothiazolyl, imidazolyl, pyrimidyl,pyrazyl, pyridazyl, thiadiazolyl, quinolyl, isoquinolyl,5,6,7,8-tetrahydroquinolyl, 1,3-dioxolopyridyl, benzimidazolyl andbenzthiazolyl.

Particular heteroaryl groups are 2-furyl, 2-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-thiazolyl, 2-imidazolyl, 2-pyrimidyl, 2-pyrazyl,3-pyridazyl, 3-quinolyl and 1-isoquinolyl optionally substituted by oneor more lower alkyl or lower alkoxy groups. Specific heteroaryl groupsare 2-furyl, 3-pyridyl, 6-methyl-3-pyridyl, 5,6-dimethyl-3-pyridyl,6-methoxy-3-pyridyl, 2-methoxy-4-pyridyl, 4-methoxy-2-pyridyl,4-hydroxy-2-pyridyl, 6-hydroxy-3-pyridyl, 2-hydroxy-4-pyridyl,N-oxo-3-pyridyl and N-oxo-6-methyl-3-pyridyl.

Preferably X is oxygen.

Preferably Z is hydrogen.

Preferably R¹ and R² are both hydrogen.

Preferably Y is oxygen.

Preferably n is 3 to 6, particularly 5 or 6.

When B is an optionally substituted phenyl group it is preferablysubstituted by one or more lower alkoxy groups, and in particular is3-methoxyphenyl or 3,4-dimethoxyphenyl.

A particularly valuable group of compounds are those in which B is a6-(2,3-dihydro-1,4-benzodioxinyl) or 5-(1,3-benzodioxolyl) group.

Preferably in the compounds of Structure 1 either A is an alkylenegroup, for example 1,1-ethanediyl (═CHCH₃), 1,2-ethanediyl (--CH₂ CH₂--), 1,3-propanediyl (--CH₂ CH₂ CH₂ --) and especially methylene (--CH₂--), or A is oxymethyl (--OCH₂ --) where p is 0, W is oxygen and q is 1.

Examples of specific compounds are:

2-[5-(S-isothioureido)pentylamino]-5-(3-pyridylmethyl)-4-pyrimidone,

2-[6-(S-isothioureido)hexylamino]-5-(3-pyridylmethyl)-4-pyrimidone,

2-[5-(O-isoureido)pentylamino]-5-(3-pyridylmethyl)-4-pyrimidone, and

2-[5-(O-isoureido)pentylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone.

The compounds of Structure 1 are shown and described as 4-pyrimidone and4-thione derivatives and these derivatives exist in equilibrium with thecorresponding 6-one and 6-thione tautomers. These compounds also existto a lesser extent as the mercapto and hydroxy tautomers, and thepyrimidine ring may also exist in the following tautomeric forms:##STR2##

The isothioureido and isoureido groups can also exist in tautomericforms, and it will be understood that all these tautomeric forms arewithin the scope of the present invention.

Hydrates and hydrated acid addition salts of compounds of Structure 1are also within the scope of this invention.

This invention includes the obvious chemical equivalents of thecompounds of Structure 1, for example, those compounds in which the--(CH₂)_(n) --group has additional substituents which do notsubstantially qualitatively affect the essential utility possessed bythe compounds of Structure 1.

The compounds of Structure 1 can be prepared by reacting a compound ofStructure 2 ##STR3## where D is HY-- or a leaving group, with (a) when Dis HY--, an isothiourea of Structure 3, in which E is lower alkyl oraryl(lower alkyl) (for example benzyl), or a cyanamide R¹ HNCN orcarbodiimide R¹ N═C═NR², or (b) when D is a leaving group, a urea orthiourea of Structure 4 ##STR4##

Typical leaving groups are chlorine, bromine, iodine, arylsulphonyloxy(for example toluene-p-sulphonyloxy) and methanesulphonyloxy.

When a compound of Structure 2 in which D is HY-- is reacted with anisothiourea of Structure 3 preferably E in the isothiourea of Structure3 is methyl. Preferably the reaction is carried out in the presence of anon-nucleophilic base. Preferably when Y is oxygen a strong base isused, for example sodium hydride or potassium t-butoxide, in a dipolaraprotic solvent, for example dimethylformamide, and preferably thereaction is carried out at elevated temperature, for example 70° to 100°C. Preferably when Y is sulphur a base of moderate strength is used forexample potassium carbonate or triethylamine, and the reaction iscarried out at about room temperature in a lower alkanol or an aqueousmixture of a lower alkanol.

When a compound of Structure 2 in which D is HY--(HO-- or HS--) isreacted with a cyanamide R¹ HNCN or carbodiimide R¹ N═C═NR² preferablythe reaction is carried out in the presence of a copper catalyst orunder anhydrous acidic conditions, for example using a salt of thecompound of Structure 2 with one equivalent of hydrogen chloride in aninert diluent, for example benzene or toluene.

When a compound of Structure 2 in which D is a leaving group is reactedwith a urea or thiourea of Structure 4, preferably the reaction iscarried out under neutral conditions, that is using a neutral acidaddition salt of the pyrimidone of Structure 2, particularly ahydrochloride or hydrobromide and preferably under essentially anhydrousconditions. Preferably the reaction is carried out in a polar solvent,for example a lower alkanol, at an elevated temperature, for example 50°to 150° C. Preferably, when Y in Structure 4 is sulphur, D in thecompound of Structure 2 is chlorine, bromine or iodine, especiallychlorine or bromine, and when Y is oxygen preferably D is iodine ortoluene-p-sulphonyloxy.

The compounds of Structure 1 in which Y is oxygen can also be preparedby reacting a compound of Structure 6, in which G is lower alkylthio,chlorine, bromine or NO₂ NH--, with an isourea of Structure 5. ##STR5##

Preferably this reaction is carried out in an inert solvent, for examplepyridine, at an elevated temperature, for example the refluxtemperature. Preferably G is NO₂ NH-- and preferably this reaction iscarried out in pyridine or in a lower alkanol, for example ethanol or2-propanol, when the reaction is preferably carried out at the boilingpoint of the lower alkanol.

All the reactions described above involve two reactants and preferablyapproximately equimolecular amounts of the reactants are used, althoughan excess, for example a slight excess of from 1.1 to 1.5 molarequivalents or a larger excess of from 1.5 to 4 molar equivalents, ofeither reactant can be used. An excess of either reactant can be presentat the start of the reaction or can be added during the course of thereaction.

The intermediates of Structure 5 can be prepared by reacting anisothiourea of Structure 3 with an aminoalcohol of formula HO(CH₂)_(n)NH₂ and a strong base. Preferably this reaction is carried out usingsodium hydride as the strong base. Preferably this reaction is carriedout using dioxan or tetrahydrofuran as solvent.

The intermediates of Structure 5 in which R¹ and R² are hydrogen orlower alkyl can be prepared by treating cyanamide, an alkylcyanamide ora N,N'-dialkylcarbodiimide with a hydrohalide salt of an aminoalcohol orformula HO(CH₂)_(n) NH₂ under anhydrous acidic conditions, or in thepresence of a copper catalyst.

The intermediates of Structure 2 in which X is oxygen and D is a leavinggroup can be prepared from the corresponding alcohols of Structure 2 inwhich D is HO--, e.g. by treatment with thionyl chloride or bromide,toluene-p-sulphonyl chloride or methanesulphonyl chloride or treatmentof the chloro compound sodium iodide. The alcohols of Structure 2 inwhich D is HO-- and X is oxygen can be prepared by reacting a compoundof Structure 6 with an α,ω-aminoalkanol HO(CH₂)_(n) NH₂.

The compounds of Structure 6 in which X is oxygen and G is nitroaminocan be prepared by reacting a β-oxoester of Structure 7, ##STR6## inwhich R is lower alkyl, with nitroguanidine.

Preferably this reaction is carried out in the presence of a base, forexample an alkali metal hydroxide or lower alkoxide or sodium hydride.

The pyrimid-4-thiones of Structure 6 in which X is sulphur and G islower alkylthio, chlorine or bromine, can be prepared by the alkalinehydrolysis, for example with sodium hydroxide in aqueous methanol, ofthe corresponding S-pyrimidyl di(lower alkyl)thiocarbamate. TheS-pyrimidyl di(lower alkyl)thiocarbamates can be prepared by reacting apyrimidone of Structure 6 in which X is oxygen with a di(loweralkyl)thiocarbamyl chloride and a base, for example sodium hydride, andheating the product, for example at 180° for 30 minutes, until it hasrearranged from an O- to a S-pyrimidyl thiocarbamate.

Compounds of Structure 6 in which G is chlorine, bromine or NO₂ NH-- andB is N-oxopyridyl can be prepared by reacting the corresponding compoundof Structure 6 in which B is pyridyl with a peroxycarboxylic acid, forexample 3-chloroperoxybenzoic acid, peroxybenzoic acid or peraceticacid.

The compounds of Structure 1 block histamine H₂ -receptors; for example,they inhibit histamine-stimulated secretion of gastric acid from thelumen-perfused stomachs of rats anaesthetised with urethane, at doses offrom 0.1 to 256 micromoles per kilogram intravenously. This procedure isreferred to in Ash and Schild, Brit. J. Pharmac. Chemother. 27, 427(1966). The 5 specific compounds described as the products of Examples 1to 5 were found to produce 50% inhibition at intravenous doses of lessthan 1 micromole per kilogram. Their activity as histamine H₂-antagonists is also demonstrated by their ability to inhibit otheractions of histamine which, according to the above mentioned paper ofAsh and Schild, are not mediated by histamine H₁ -receptors. Forexample, they inhibit the actions of histamine on the isolated guineapig atrium and isolated rat uterus. They inhibit the basal secretion ofgastric acid and also that stimulated by pentagastrin or by food. In aconventional test such as the measurement of blood pressure in theanaesthetised cat, at doses of from 0.5 to 256 micromoles per kilogramintravenously, they inhibit the vasodilator action of histamine. Thepotency of these compounds is illustrated by the effective doseproducing 50% inhibition of gastric acid secretion in the anaesthetisedrat and the dose producing 50% inhibition of histamine-inducedtachycardia in the isolated guinea pig atrium (less than 10⁻⁴ Molar).

The compounds of Structure 1 also block histamine H₁ -receptors, that isthey inhibit the biological actions of histamine which are inhibited bymepyramine, diphenhydramine and chlorpheniramine. For example theyinhibit the histamine-stimulated contractions of the isolated guinea-pigileum at doses of about 10⁻⁵ Molar. Their combined histamine H₁ - and H₂-antagonist activity is useful for treatment of inflammation inconditions where histamine is a mediator of inflammation, for instancein skin inflammation. Their combined histamine H₁ - and H₂ -activity isalso useful in those circumstances where there are hypersensitivityresponses, for example, allergies, due to the action of histamine atH₁ - and H₂ -receptors. It is advantageous to administer a singlecompound having histamine H₁ - and H₂ -antagonist activity rather thanto administer individual compounds having histamine H₁ -antagonistactivity and histamine H₂ -antagonist activity as difficulties arisingfrom differing rates of absorption and pharmacokinetic characteristicsare avoided.

The compounds of Structure 1 show anti-inflammatory activity inconventional tests such as the rat or mouse paw oedema and theguinea-pig U.V. erythema tests. In the former tests the oedema isinduced by an irritant, for example carrageenan, and in the latter testthe depilated skin of the guinea-pig is exposed to U.V. radiation and anerythema results. Subcutaneous injection of doses of the compound ofStructure 1 reduces the rat or mouse paw volume in the former tests andreduces the intensity of the guinea-pig erythema in the latter test. Auseful modification of the guinea-pig U.V. erythema test is to irradiateonly the whole ear and measure the ear temperature by a thermistorprobe. Subcutaneous injection of doses of about 0.2 mmol/kg of acompound of Structure 1 to a guinea-pig reduces the rise in eartemperature caused by U.V. irradiation. These compounds show a sustainedanti-inflammatory activity in this test greater than that which mayreasonable be attributed to blockade of histamine receptors. Activity inthis animal test is indicative that the compounds will be useful intreating inflammatory conditions in humans.

The pharmaceutical compositions of the invention comprise apharmaceutical carrier and a pharmacologically-active compound ofStructure 1 which can be in the base form or in the form of apharmaceutically acceptable acid addition salt. Such addition saltsinclude those with hydrochloric, hydrobromic, hydriodic, sulphuric andmaleic acids and may conveniently be formed from the correspondingcompounds of Structure 1 by standard procedures, for example by treatingthem with an acid in a lower alkanol or by the use of ion-exchangeresins to form the required salt either directly from the compound inthe base form from a different addition salt. Preferably the compoundsof Structure 1 in which Y is sulphur are used in the form of acidaddition salts and compounds in which Y is oxygen are used in the formof the free bases.

The pharmaceutical carrier employed can be a solid or liquid. Examplesof solid carriers are lactose, maize starch, potato starch, or modifiedstarches, dicalcium phosphate, terra alba, sucrose, celluloses, talc,gelatin, agar, pectin, acacia, magnesium stearate and stearic acid.Examples of liquid carriers are syrup, peanut oil, olive oil, alcohol,propylene glycol, polyethylene glycols and water.

If a solid carrier is used, the composition can be prepared in the formof a tablet, capsule containing powder or pellets, troche or lozenge.The amount of solid carrier in a unit dosage form is generally fromabout 25 mg to about 300 mg. If a liquid carrier is used, thecomposition can be in the form of a syrup, emulsion, multiple emulsion,sterile injectable liquid or an aqueous or non-aqueous solution orliquid suspension. Other additives such as preservatives, for exampleantioxidants or antibacterials, and/or flavouring of colouring agentscan also be included. The sterile liquids can be prepared in ampoules,multidose vials or unit dose disposable systems. The preparation canalso be in a semi-solid form, for example a cream, paste, ointment orgel, or in a liquid or aerosol form for topical application. Thepharmaceutical compositions are prepared by conventional techniquesinvolving procedures such as milling, mixing, granulating andcompressing, spray drying, freeze drying or dissolving or dispersing theingredients as appropriate to the desired preparation. The activeingredient will be present in the compositions in an effective amount toproduce the desired activity. Preferably, each dosage unit will containthe active ingredient in an amount of from about 50 mg to about 250 mg.

The invention provides a method of producing antiinflammatory activitywhich comprises administering to an animal an active compound ofStructure 1. The active ingredient will preferably be administered oneto six times per day. The invention also provides a method of blockinghistamine H₂ -receptors and a method of simultaneously blockinghistamine H₁ - and H₂ -receptors which comprises administering to ananimal an active compound of Structure 1. The active compound will beadministered in an effective amount to product said activity. The dailydosage regiment will preferably be from about 150 mg to about 1500 mg.The route of administration may be oral, parenteral or, whenappropriate, topical.

The invention is illustrated by the following Examples, in whichtemperature are in °C.:

EXAMPLE 1

(i) 2-Methylthio-5-(3-pyridylmethyl)-4-pyrimidone (23.3 g) and5-aminopentanol (24.5 g) were fused together at 170°-180° for 2 hours.Water was added to the cooled residue and the mixture was adjusted topH7 with dilute hydrochloric acid. The solid (23.8 g) which crystallisedout was recrystallised from 2-propanol containing hydrogen chloride togive 2-(5-hydroxypentylamino)-5-(3-pyridylmethyl)-4-pyrimidonedihydrochloride, m.p. 203°-205°.

(ii) 2-(5-Hydroxypentylamino)-5-(3-pyridylmethyl)-4-pyrimidonedihydrochloride (1.9 g) was heated under reflux in thionyl chloride (25ml) for 45 minutes. The mixture was evaporated to dryness to give crude2-(5-chloropentylamino)-5-(3-pyridylmethyl)-4-pyrimidonedihydrochloride, which was treated with thiourea (0.47 g) dissolved inthe minimum volume of hot ethanol. The ethanol was boiled off and theresidue was heated at 160° for 4 hours. The residue was extracted withboiling ethanol and the extract cooled. The solid (1.85 g) whichcrystallised out was dissolved in water, the solution was adjusted topH7-7.5 with aqueous sodium hydroxide and this solution was extractedwith chloroform. The aqueous phase was evaporated to a residue which wasextracted with 2-propanol and the extract was evaporated to give2-[5-(S-isothioureido)pentylamino]-5-(3-pyridylmethyl)-4-pyrimidonemonohydrochloride as an oil which was treated with hydrogen chloride inethanol and crystallised from methanol-ethanol to give2-[5-(S-isothioureido)pentylamino]-5-(3-pyridylmethyl)- 4-pyrimidonetrihydrochloride (1.5 g) m.p. 228°-9°.

EXAMPLE 2

(i) Substitution of 6-aminohexanol for 5-aminopentanol in the procedureof Example 1(i) gave2-(6-hydroxyhexylamino)-5-(3-pyridylmethyl)-4-pyrimidone, m.p.131°-133°.

(ii) Substitution of2-(6-hydroxyhexylamino)-5-(3-pyridylmethyl)-4-pyrimidone for2-(5-hydroxypentylamino)-5-(3-pyridylmethyl)-4-pyrimidone in theprocedure of Example 1(ii) gave2-[6-(isothioureido)hexylamino]-5-(3-pyridylmethyl)-4-pyrimidonetrihydrochloride, which was dissolved in water and passed down anAmberlite IRA 400 ion-exchange resin (acetate form). Amberlite IRA 400is a quaternary ammonium ion-exchange resin with a matrix of 8%cross-linked polystyrene-divinylbenzene. The solution was evaporated todryness and the residue was recrystallised from methanol-ether to give2-[6-(S-isothioureido)hexylamino]-5-(3-pyridylmethyl)-4-pyrimidone,acetic acid salt, m.p. 160°-163°.

EXAMPLE 3

Dry hydrogen chloride (1.7 g) was added to a suspension of2-(5-hydroxypentylamino)-5-(3-pyridylmethyl)-4-pyrimidonedihydrochloride (13.0 g) and cyanamide (3.0 g) in dry benzene (100 ml)and the mixture was allowed to stand at room temperature for 5 days.Cyanamide (1.5 g) was added, the mixture was thoroughly stirred and wasleft to stand at room temperature for a further 7 days. The benzene wasdecanted off and the solid was dissolved in water (150 ml). The solutionwas adjusted to pH7.5 and extracted with n-butanol (4×250 ml) andaqueous extracts (6×100 ml) were made of the butanol extracts using acountercurrent distribution technique. The aqueous extracts wereconcentrated, acidified with hydrochloric acid and passed down inAmberlite IRA 400 (Bromide form) ion-exchange column. The eluent wasevaporated to dryness and the residue was crystallised fromethanol/2-propanol to give2-[5-(O-isoureido)pentylamino]-5-(3-pyridylmethyl)-4-pyrimidonetrihydrobromide, m.p. 158°-160° (decomp). This is converted into thefree base by passage down a quaternary ammonium ion-exchange resin inthe OH⁻ form.

EXAMPLE 4

Substitution of an equivalent amount of N, N'-dimethylthiourea forthiourea in the procedure of Example 1(ii) gave2-[5-(N,N'-dimethyl-S-isothioureido)pentylamino]-5-(3-pyridylmethyl)-4-pyrimidone trihydrochloridemonohydrate, as a glass, m.p. indeterminate.

    __________________________________________________________________________    100 MHz .sup.1 H n.m.r. (D.sub.2 O):δ                                                 ˜1.70                                                                         (CH.sub.2).sub.3                                                                        m   (6.0)                                                      3.06, 3.11                                                                         NCH.sub.3                                                                              2s                                                                                 (8.4)                                                     ˜3.21                                                                         SCH.sub.2                                                                               m                                                             ˜3.50                                                                         CH.sub.2 N                                                                              m   (2.0)                                                      4.01                                                                                ##STR7##                                                                               s   (2.0 ref)                                                  7.84                                                                                ##STR8##                                                                               s   (1.0)                                                      8.09 Pyr 5-H   d of d                                                                            (1.0)                                                      8.61 Pyr 4-H   m                                                                                 (3.0)                                                     ˜8.75                                                                         Pyr 2-H + 6-H                                                                           m                                               __________________________________________________________________________

EXAMPLE 5

(i) 3-(6-Methyl-3-pyridyl)propenoic acid, m.p. 213.5°-215.5°, wasprepared by reacting 6-methylpyridine-3-carboxaldehyde with malonic acidin pyridine with piperidine catalyst, and was converted into thecorresponding ethyl ester m.p. 36°-37° which was reduced with hydrogenand palladium-on-charcoal catalyst to give ethyl3-(6methyl-3-pyridyl)-propionate (oil). This ester was reacted withsodium and ethyl formate and the product treated with thiourea to give5-(6-methyl-3-pyridylmethyl)-2-thiouracil m.p. 240°-241° which wasalkylated with methyl iodide in the presence of sodium hydroxide at 70°to give 5-(6-methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidone, m.p.197°-198.5°.

(ii) Reaction of 5-(6-methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidonewith 5-aminopentanol at 170°-180° gave2-(5-hydroxypentylamino)-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone whichwas isolated as the dihydrochloride salt m.p. 215°-217°.

(iii) Substitution of2-(5-hydroxypentylamino)-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone for2-(5-hydroxypentylamino)-5-(3-pyridylmethyl)-4-pyrimidone in the generalprocedure of Example 3 gave2-[5-(O-isoureido)pentylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidonetrihydrobromide monohydrate m.p. 110°-115° (from ethanol/2-propanol).

    __________________________________________________________________________    .sup.1 H n.m.r (100 MHz, D.sub.2 O):-δ                                                 1.70                                                                             CH.sub.2 m   (6.1)                                                         2.77                                                                             CH.sub.3 s   (3.0 ref)                                                     3.46                                                                             NCH.sub.2                                                                              m   (2.1)                                                         3.90                                                                              ##STR9##                                                                              s   (1.8)                                                         4.30                                                                             OCH.sub.2                                                                              m   (obscured                                                                     by D.sub.2 O)                                                 7.74                                                                             Pyrim 6-H                                                                              s                                                                                 (2.0)                                                         7.84                                                                             Pyr5-H   d                                                                 8.39                                                                             Pyr4-H   m                                                                                 (2.0)                                                         8.56                                                                             Pyr2-H   m                                                  __________________________________________________________________________

This is converted into the free base by passage down a quaternaryammonium ion-exchange resin in the OH⁻ form.

EXAMPLE 6

Treatment of 5-(6-methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidone with6-aminohexanol gives2-(6-hydroxyhexylamino)-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone whichmay be successively treated with thionyl chloride and thiourea accordingto the general procedure of Example 1(ii) to give2-[6-(S-isothioureido)hexylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidonetrihydrochloride.

EXAMPLE 7

Substitution of2-(6-hydroxyhexylamino)-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone for2-(5-hydroxypentylamino)-5-(3-pyridylmethyl)-4-pyrimidone in the generalprocedure of Example 3 gives2-[6-(O-isoureido)hexylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone.

EXAMPLE 8

When 2-(5-hydroxypentylamino)-5-(6-methyl-3-pyridylmethyl)-4-pyrimidoneis successively reacted with thionyl chloride and thiourea according tothe general procedure of Example 1(ii) the product is2-[5-(S-isothioureido)pentylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidonetrihydrochloride.

EXAMPLES 9 AND 10

(i) Reaction of5-[5-(1,3-benzodioxolyl)methyl]-2-methylthio-4-pyrimidone with

(a) 5-aminopentanol

(b) 6-aminohexanol

(a)2-[5-(S-isothioureido)pentylamino]-5-[5-(1,3-benzodioxolyl)methyl]-4-pyrimidone

(b)2-[6-(S-isothioureido)hexylamino]-5-[5-(1,3-benzodioxolyl)methyl]-4-pyrimidone

(ii) Substitution of

(a)2-(5-hydroxypentylamino)-5-[5-(1,3-benzodioxolyl)methyl]-4-pyrimidone

(b) 2-(6-hydroxyhexylamino)-5-[5-(1,3-benzodioxolyl)methyl]-4-pyrimidone

for 2-(5-hydroxypentylamino)-5-(3-pyridylmethyl)-4-pyrimidone in thegeneral procedure of Example 3 gives

9(a)2-[5-(O-isoureido)pentylamino]-5-[5-(1,3-benzodioxolyl)methyl]-4-pyrimidon

10(b)2-[6-(O-isoureido)hexylamino]-5-[5-(1,3-benzodioxolyl)methyl]-4-pyrimidone

EXAMPLE 11

(i) Ethyl 3-(6-methyl-3-pyridyl)propionate was reacted at 0° with ethylformate and sodium hydride in 1,2-dimethoxyethane to give ethyl2-formyl-3-(6-methyl-3-pyridyl)propionate, m.p. 142°-144°, which washeated under reflux with dried nitroguanidine and sodium methoxide inmethanol to give 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone,m.p. 215°-6° (decomp).

(ii) Reaction of 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidonewith 5-aminopentanol in refluxing pyridine gives2-(5-hydroxypentylamino)-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone whichcan be converted into2-[5-(O-isoureido)pentylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidoneby the procedure of Example 5(iii).

EXAMPLE 12

S-Methylisothiourea is reacted with 5-aminopentanol and sodium hydridein tetrahydrofuran to give O-(5-aminopentyl)isourea, which is reactedwith 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone in refluxingethanol to give2-[5-(O-isoureido)pentylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone.

EXAMPLES 13 TO 16

2-(5-Hydroxypentylamino)-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone isreacted with

(a) 1,4,5,6-tetrahydro-2-methylthiopyrimidine

(b) 4,5-dihydro-2-methylthioimidazole

(c) N,S-dimethylisothiourea

(d) N,N'-dibutyl-S-methylisothiourea and sodium hydride indimethylformamide to give Example

13.2-[5-(1,4,5,6-tetrahydro-2-pyrimidyloxy)pentylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone

14.2-[5-(4,5-dihydro-2-imidazolyloxy)pentylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone

15.2-[5-(N-methyl-S-isothioureido)pentylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone

16.2-[5-(N,N'-dibutyl-S-isothioureido)pentylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone

EXAMPLE 17 TO 19

Reaction of 2-methylthio-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone with

(a) 3-aminopropanol

(b) 7-aminoheptanol

(c) 8-aminooctanol

at 160° gives

(a) 2-(3-hydroxypropylamino)-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone

(b) 2-(7-hydroxyheptylamino)-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone

(c) 2-(8-hydroxyoctylamino)-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone

which are reacted with cyanamide and hydrogen chloride to give Example

17.2-[3-(O-isoureido)propylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone

18.2-[7-(O-isoureido)heptylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone

19.2-[8-(O-isoureido)octylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone

EXAMPLES 20 AND 21

Reaction of 5-aminopentanol at 160° with

(a) 6-methyl-2-methylthio-5-(3-pyridylmethyl)-4-pyrimidone

(b) 2-methylthio-5-(1-(3-pyridyl)ethyl)-4-pyrimidone

gives

(a) 2-(5-hydroxypentylamino)-6-methyl-5-(3-pyridylmethyl)-4-pyrimidone

(b) 2-(5-hydroxypentylamino)-5-(1-(3-pyridyl)ethyl)-4-pyrimidone

which are reacted with cyanamide and hydrogen chloride to give Example

20.2-[5-(O-isoureido)pentylamino]-6-methyl-5-(3-pyridylmethyl)-4-pyrimidone

21. 2-[5-(O-isoureido)pentylamino)-5-(1-(3-pyridyl)ethyl)-4-pyrimidone

EXAMPLE 22

5-(6-Methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidone is reacted withdimethylthiocarbamyl chloride and sodium hydride to giveO-[5-(6-methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidyl]dimethylthiocarbamate.This is heated at 180° for 30 minutes to giveS-[5-(6-methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidyl]dimethylthiocarbamatewhich is treated with sodium hydroxide in methanol to give5-(6-methyl-3-pyridylmethyl)-2-methylthiopyrimid-4-thione, which isheated with 5-aminopentanol at 150° to give2-(5-hydroxypentylamino)-5-(6-methyl-3-pyridylmethyl)pyrimid-4-thione.This is reacted with cyanamide and hydrogen chloride to give2-[5-(O-isoureido)pentylamino]-5-(6-methyl-3-pyridylmethyl)-pyrimid-4-thione.

EXAMPLE 23

(i) Ethyl formate and 2-butanone are added to sodium hydride andcyanoacetamide is added to give 3-cyano-5, 6-dimethyl-2-hydroxypyridine,which is reacted with phosphorus pentachloride and the product reducedwith hydrogen and Raney nickel in the presence of semicarbazide, andformaldehyde is added to the mixture to give2-chloro-5,6-dimethyl-3-pyridinecarboxaldehyde m.p. 69°-70°.

(ii) 2-Chloro-5,6-dimethyl-3-pyridinecarboxaldehyde is condensed withmalonic acid and the product is esterified and reduced with hydrogen at344 kPa using palladium-on-charcoal catalyst to give ethyl3-(5,6-dimethyl-3-pyridyl)propionate as an oil. This oil is reacted withethyl formate and sodium hydride at room temperature to give the2-formyl derivative, m.p. 148°-9°, which is heated under reflux withnitroguanidine and sodium methoxide to give5-(5,6-dimethyl-3-pyridylmethyl)-2-nitroamino-4-pyrimidone, m.p.212°-3°.

(iii) 5-(5,6-Dimethyl-3-pyridylmethyl)-2-nitroamino-4-pyrimidone isreacted with 5-aminopentanol in refluxing ethanol to give2-(5-hydroxypentylamino)-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidonewhich is reacted with cyanamide and hydrogen chloride to give2-[5-(O-isoureido)pentylamino]-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone.

EXAMPLES 24 TO 29

(i) Reduction of 2-methoxy-5-cyanopyridine with hydrogen and Raneynickel in the presence of semicarbazide, and treatment of the mixturewith formaldehyde gives 6-methoxypyridine-3-carboxaldehyde, m.p. 48°-9°.In a similar manner 2-methoxypyridine-4-carboxaldehyde, m.p. 33°-6° isprepared from 2-methoxy-4-cyanopyridine (which is prepared from2-chloro-4-cyanopyridine and sodium methoxide).

(ii) Condensation of

(a) 6-methoxypyridine-3-carboxaldehyde

(b) 2-methoxypyridine-4-carboxaldehyde

(c) 4-methoxypyridine-2-carboxaldehyde

with malonic acid and esterification and reduction of the product withhydrogen and palladium-on-charcoal gives the corresponding3-(pyridyl)propionates which are formylated with ethyl formate andsodium hydride and the product reacted with nitroguanidine and sodiummethoxide to give

(a) 2-nitroamino-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone m.p.183.5°-186°.

(b) 2-nitroamino-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone m.p.194°-195.5°.

(c) 2-nitroamino-5-(4-methoxy-2-pyridylmethyl)-4-pyrimidone m.p.196°-8°.

(iii) Reaction of the above 2-nitroamino-4-pyrimidones with5-aminopentanol gives the corresponding2-(5-hydroxypentylamino)-4-pyrimidones which are reacted withS-methyisothiourea and sodium hydride to give

24.2-[5-(O-isoureido)pentylamino]-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone.

25.2-[5-(O-isoureido)pentylamino]-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone.

26.2-[5-(O-isoureido)pentylamino)-5-(4-methoxy-2-pyridylmethyl)-4-pyrimidone

(iv) Heating the above 2-[5-(O-isoureido)pentylamino]-4-pyrimidones with2 N hydrogen chloride in methanol gives

27.2-[5-(O-isoureido)pentylamino]-5-(6-hydroxy-3-pyridylmethyl)-4-pyrimidone.

28.2-[5-(O-isoureido)pentylamino]-5-(2-hydroxy-4-pyridylmethyl)-4-pyrimidone.

29.2-[5-(O-isoureido)pentylamino]-5-(4-hydroxy-2-pyridylmethyl)-4-pyrimidone.

EXAMPLE 30

(i) Reaction of 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidonewith 3-chloroperoxybenzoic acid in acetic acid gave2-nitroamino-5-(N-oxo-6-methyl-3-pyridylmethyl)-4-pyrimidone, m.p. 232°(decomp.) which is reacted with 5-aminopentanol to give2-(5-hydroxypentylamino)-5-(N-oxo-6-methyl-3-pyridylmethyl)-4-pyrimidone.

(ii) Reaction of the latter compound with cyanamide and hydrogenchloride gives2-[5-(O-isoureido)pentylamino]-5-(N-oxo-6-methyl-3-pyridylmethyl)-4-pyrimidone.

EXAMPLES 31 TO 41

Reaction of the 2-(ω-hydroxyalkylamino)-4-pyrimidone derivativesdescribed in Examples 17 to 23 and 30 with thionyl chloride andsubsequent reaction with thiourea gives

31.2-[3-(5-isothioureido)propylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone.

32.2-[7-(S-isothioureido)heptylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone.

33.2-[8-(S-isothioureido)octylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone.

34.2-[5-(S-isothioureido)pentylamino]-6-methyl-5-(3-pyridylmethyl)-4-pyrimidone.

35.2-[5-(S-isothioureido)pentylamino]-5-(1-(3-pyridyl)ethyl)-4-pyrimidone.

36.2-[5-(S-isothioureido)pentylamino]-5-(6-methyl-3-pyridylmethyl)-pyrimid-4-thione.

37.2-[5-(S-isothioureido)pentylamino]-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone.

38.2-[5-(S-isothioureido)pentylamino]-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone.

39.2-[5-(S-isothioureido)pentylamino]-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone.

40.2-[5-(S-isothioureido)pentylamino]-5-(4-methoxy-2-pyridylmethyl)-4-pyrimidone.

41.2-[5-(S-isothioureido)pentylamino]-5-(N-oxo-6-methyl-3-pyridylmethyl)-4-pyrimidone.

EXAMPLES 42 TO 44

Heating the 5-(methoxypyridylmethyl)-4-pyrimidones of Examples 37 to 39with 2 N hydrogen chloride in methanol gives

42.2-[5-(S-isothioureido)pentylamino]-5-(6-hydroxy-3-pyridylmethyl)-4-pyrimidone.

43.2-[5-(S-isothioureido)pentylamino]-5-(2-hydroxy-4-pyridylmethyl)-4-pyrimidone.

44.2-[5-(S-isothioureido)pentylamino]-5-(4-hydroxy-2-pyridylmethyl-4-pyrimidone.

EXAMPLE 45

Reaction of 5-aminopentanol with

(a) 5-(1-naphthylmethyl)-2-methylthio-4-pyrimidone

(b) 5-(3-quinolylmethyl)-2-methylthio-4-pyrimidone gives thecorresponding 2-(5-hydroxypentylamino)-4-pyrimidones were are reactedwith cyanamide and hydrogen chloride to give

(a) 2-[5-(O-isoureido)pentylamino]-5-(1-naphthylmethyl)-4-pyrimidone

(b) 2-[5-(O-isoureido)pentylamino]-5-(3-quinolylmethyl)-4-pyrimidone

EXAMPLE 46

Reaction of 5-aminopentanol with

(a) 5-(2-pyridylmethyl)-2-methylthio-4-pyrimidone

(b) 5-(4-pyridylmethyl)-2-methylthio-4-pyrimidone

(c) 5-(2-thienylmethyl)-2-methylthio-4-pyrimidone

(d) 5-(4-methylbenzyl)-2-methylthio-4-pyrimidone

(e) 5-(3,4,5-trimethoxybenzyl)-2-methylthio-4-pyrimidone

(f) 5-(4-chlorobenzyl)-2-methylthio-4-pyrimidone

(g) 5-(2-chlorobenzyl)-2-methylthio-4-pyrimidone

(h) 5-(3,4-dichlorobenzyl)-2-methylthio-4-pyrimidone

gives the corresponding 2-(5-hydroxypentylamino)-4-pyrimidone which arereacted with cyanamide and hydrogen chloride to give

(a) 2-[5-(O-isoureido)pentylamino]-5-(2-pyridylmethyl)-4-pyrimidone

(b) 2-[5-(O-isoureido)pentylamino]5-(4-pyridylmethyl)-4-pyrimidone

(c) 2-[5-(O-isoureido)pentylamino]-5-(2-thienylmethyl)-4-pyrimidone

(d) 2[5-(O-isoureido)pentylamino]-5-(4-methylbenzyl)-4-pyrimidone

(e)2-[5-(O-isoureido)pentylamino]-5-(3,4,5-trimethoxybenzyl)-4-pyrimidone

(f) 2-[5-(O-isoureido)pentylamino]-5-(4-chlorobenzyl)-4-pyrimidone

(g) 2-[5-(O-isoureido)pentylamino]-5-(2-chlorobenzyl)-4-pyrimidone

(h) 2-[5-(O-isoureido)pentylamino]-5-(3,4-dichlorobenzyl)-4-pyrimidone

EXAMPLE 47

Reaction of 5-aminopentanol with

(a) 5-benzyloxy-2-methylthio-4-pyrimidone

(b) 5-(2-(4-methoxybenzyloxy)ethyl)-2-methylthio-4-pyrimidone

(c) 5-(2-(4-methoxybenzylthio)ethyl)-2-methylthio-4-pyrimidone

(d) 5-(2-(3-pyridylmethylthio)ethyl)-2-methylthio-4-pyrimidone

(e) 5-(2-phenylethyl)-2-methylthio-4-pyrimidone

(f) 5-(2-phenylethyl)-6-methyl-2-methylthio-4-pyrimidone

(g) 5-(4-phenylbutyl)-2-methylthio-4-pyrimidone gives the corresponding2-(5-hydroxypentylamino)-4-pyrimidones which are reacted with cyanamideand hydrogen chloride or S-methylisothiourea and sodium hydride to give

(a) 2-[5-(O-isoureido)pentylamino]-5-benzyloxy-4-pyrimidone

(b)2-[5-(O-isoureido)pentylamino]-5-(2-(4-methoxybenzyloxy)ethyl)-4-pyrimidone

(c)2-[5-(O-isoureido)pentylamino]-5-(2-(4-methoxybenzylthio)ethyl)-4-pyrimidone

(d)2-[5-(O-isoureido)pentylamino]-5-(2-(3-pyridylmethylthio)ethyl)-4-pyrimidone

(e) 2-[5-(O-isoureido)pentylamino]-5-(2-phenylethyl)-4-pyrimidone

(f)2-[5-(O-isoureido)pentylamino]-5-(2-phenylethyl)-6-methyl-4-pyrimidone

(g) 2-[5-(O-isoureido)pentylamino]-5-(4-phenylbutyl)-4-pyrimidone

EXAMPLE 48

Substitution of the following 3-(heteroaryl)propionates:

(a) ethyl 3-(2-methoxy-3-pyridyl)propionate

(b) ethyl 3-(4,6-dimethoxy-3-pyridyl)propionate

(c) ethyl 3-(2,6-dimethoxy-4-pyridyl)propionate

(d) ethyl 3-(4,5-dimethoxy-2-pyridyl)propionate

(e) ethyl 3-(5-hydroxy-2-pyridyl)propionate

(f) ethyl 3-(4-hydroxy-2-pyrimidyl)propionate

(g) ethyl 3-(4-hydroxy-5-methoxy-2-pyridyl)propionate

(h) ethyl 3-(4-hydroxy-3-methoxy-2-pyridyl)propionate

(i) ethyl 3-(4,5-dimethyl-2-thienyl)propionate

(j) ethyl 3-(6-amino-3-pyridyl)propionate

(k) ethyl 3-(4-isoquinolyl)propionate

(l) ethyl 3-(3-chloro-2-pyridyl)propionate

for ethyl 3-(6-methyl-3-pyridyl)propionate in the procedure of Example5(i)-(iii) gives the corresponding2-[5-(O-isoureido)pentylamino]-5-(heteroarylmethyl)-4-pyrimidones.

The starting materials may be prepared by condensing the correspondingheterocyclic carboxyaldehyde with (i) malonic acid, and hydrogenatingand esterifying the products or (ii) diethyl malonate, reducing theproduct with sodium borohydride followed by hydrolysis,monodecarboxylation and esterification, or by reacting ahalomethylheterocyclic derivative with sodium and diethyl malonate, andhydrolysing, monodecarboxylating and esterifying the product.

EXAMPLE 49

Substitution of the following 3-arylpropionates:

(a) ethyl 3-(6-(2,3-dihydro-1,4-benzodioxinyl)propionate

(b) ethyl 3-(3-benzyloxyphenyl)propionate

(c) ethyl 3-(3-methoxymethoxyphenyl)propionate (prepared by reactingethyl 3-(3-hydroxyphenyl)propionate with dimethoxymethane)

(d) ethyl 3-(3-trifluoromethylphenyl)propionate

(e) ethyl 3-(4-dimethylaminophenyl)propionate

(f) ethyl 3-(4-phenoxyphenyl)propionate

(g) ethyl 3-(4-(4-chlorophenoxy)phenyl)propionate

(h) ethyl 3-(4-(4-methoxyphenoxy)phenyl)propionate

(i) ethyl 3-(4-biphenylyl)propionate

(j) ethyl 3-(4'-chloro-4-biphenylyl)propionate

(k) ethyl 3-(4'-methoxy-4-biphenylyl)propionate

for ethyl 3-(6-methyl-3-pyridyl)propionate in the procedure of Example5(i)-(iii) gives the corresponding2-[5-(O-isoureido)pentylamino]-5-(arylmethyl)-4-pyrimidones.

Treatment of the product from (c) with hydrochloric acid gives the5-(3-hydroxybenzyl)pyrimidone.

EXAMPLE 50

Substitution of the following 3-(heteroaryl)propionates:

(a) ethyl 3-(2-furyl)propionate

(b) ethyl 3-(2-thiazolyl)propionate

(c) ethyl 3-(5-oxazolyl)propionate

(d) ethyl 3-(3-isothiazolyl)propionate

(e) ethyl 3-(2-pyrimidyl)propionate

(f) ethyl 3-(5-pyrimidyl)propionate

(g) ethyl 3-(2-pyrazyl)propionate

(h) ethyl 3-(4-pyridazyl)propionate

(i) ethyl 3-(2-(5-amino-1,3,4-thiadiazolyl)propionate

(j) ethyl 3-(1-isoquinolyl)propionate

(k) ethyl 3-(4-(1,3-dioxolo[4,5-C]-pyridyl)propionate

(1) ethyl 3-(2-benzimidazolyl)propionate

(m) ethyl 3-(2-benzthiazolyl)propionate

for ethyl 3-(6-methyl-3-pyridyl)propionate in the procedure of Example5(i)-(iii) gives the corresponding 5-(heteroarylmethyl)-4-pyrimidones.

The starting materials can be prepared as described in Example 48.

EXAMPLE 51

Substitution of

(a) ethyl octanoate

(b) ethyl 3-cyclohexylpropionate

for ethyl 3-(6-methyl-3-pyridyl)propionate in the procedure of Example5(i)-(iii) gives

(i)

(a) 5-hexyl-2-thiouracil m.p. 169.5°-172° (from aqueous ethanol)

(b) 5-cyclohexylmethyl-2-thiouracil m.p. 210°-211° (from ethanol)

(ii)

(a) 5-hexyl-2-methylthio-4-pyrimidone m.p. 116°-117.5° (from aqueousethanol)

(b) 5-cyclohexylmethyl-2-methylthio-4-pyrimidone m.p. 187°-188° (fromacetic acid)

(iii)

(a) 2-[5-(O-isoureido)pentylamino]-5-hexyl-4-pyrimidone

(b) 2-[5-(O-isoureido)pentylamino]-5-cyclohexylmethyl-4-pyrimidone.

EXAMPLE 52

A pharmaceutical composition is prepared from the following ingredients:

2-[5-(O-isoureido)pentylamino]-5-(3-pyridylmethyl)pyrimidone: 150 mg

Sucrose: 75 mg

Starch: 25 mg

Talc: 5 mg

Stearic acid: 2 mg

The ingredients are screened, mixed and filled into a hard gelatincapsule.

Similarly the other compounds of Structure 1 can be formulated intopharmaceutical compositions by the procedure of Example 52. Thesepharmaceutical compositions are administered to a subject within thedose ranged given hereabove to block histamine H₂ - and H₁ -receptorsand to alleviate acute inflammation.

EXAMPLE 53

Preparation of a pharmaceutical composition for topical administrationcontaining

    ______________________________________                                                                  % w/w                                               ______________________________________                                                  Stearyl alcohol           15.0                                                Beeswax                   8.0                                       A         Sorbitan monooleate       1.25                                                Polyoxyethylene sorbitan monooleate                                                                     3.75                                                The product of any one of Examples 1 to 51                                                              1.0                                                 Sorbitan solution BP      7.5                                                 Citric Acid               0.2                                       B         Sodium Citrate            0.05                                                Methylparaben             0.18                                                Propylparaben             0.02                                                Water                     to 100                                    ______________________________________                                    

A mixture of the ingredients A is heated to 72°, added with stirring toa mixture of the ingredients B at 70°, and the stirring is continueduntil a cream is formed.

EXAMPLE 54

An injectable pharmaceutical composition is prepared by dissolving2-[5-(S-isothioureido)pentylamino]-5-(3-pyridylmethyl)-4-pyrimidonetrihydrochloride (100 g) in sterile water (2 liters). From it areprepared ampoules containing 100 mg of active ingredient.

We claim:
 1. A compound of the formula ##STR10## ##STR11## in which R¹and R² are hydrogen or lower alkyl;Y is sulphur or oxygen; n is from 3to 8; X is oxygen or sulphur; Z is hydrogen or lower alkyl; A isstraight or branched C₁ -C₅ alkylene or --(CH₂)_(p) W(CH₂)_(q) -- whereW is oxygen or sulphur and the sum of p and q is 1 to 4; and B ismethyl, C₃ -C₆ cycloalkyl, a heteroaryl group selected from furyl,thienyl, thiazolyl, oxazolyl, isothiazolyl, imidazolyl, thiadiazolyl,benzimidazolyl and benzthiazolyl, said heteroaryl being optionallysubstituted by one or more lower alkyl, lower alkoxy, halo, hydroxy oramino groups or B is a naphthyl, 5- or 6-(2,3-dihydro-1,4-benzodioxinyl)or 4- or 5-(1,3-benzodioxolyl) group, or a phenyl group optionallysubstituted with one or more lower alkyl, lower alkoxy, halogen,phenyl(lower alkoxy), hydroxy, lower alkoxy-lower alkoxy,trifluoromethyl, di(lower alkyl)amino, phenoxy, halophenoxy, loweralkoxyphenoxy, phenyl, halophenyl or lower alkoxyphenyl group, or,provided A is alkylene, B can be hydrogen, in the form of the free baseor a pharmaceutically acceptable acid addition salt thereof.
 2. Acompound according to claim 1 in which X is oxygen.
 3. A compoundaccording to claim 2 in which Z is hydrogen.
 4. A compound according toany one of claims 1, 2 or 3 in which R¹ and R² are both hydrogen.
 5. Acompound according to claim 1 in which Y is oxygen.
 6. A compoundaccording to claim 1 in which n is 5 or
 6. 7. A compound according toclaim 1 in which A is methylene.
 8. A pharmaceutical compositioncomprising a compound according to claim 1 and a pharmaceuticallyacceptable diluent or carrier.
 9. A method of blocking histamine H₂-receptors which comprises administering to an animal a compoundaccording to claim
 1. 10. A method of simultaneously blocking histamineH₁ -receptors and histamine H₂ -receptors which comprises administeringto an animal a compound according to claim
 1. 11. A method of producingantiinflammatory activity which comprises administering to an animal acompound according to claim 1.